A Metabolomics Approach for Predicting OATP1B-Type Transporter-Mediated Drug-Drug Interaction Liabilities

Yang Li, Yan Jin, Hanieh Taheri, Keith T. Schmidt, Alice A. Gibson, Stefan A. J. Buck, Eric D. Eisenmann, Ron H. J. Mathijssen, William D. Figg, Sharyn D. Baker, Alex Sparreboom, Shuiying Hu*

*Corresponding author for this work

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Abstract

In recent years, various endogenous compounds have been proposed as putative biomarkers for the hepatic uptake transporters OATP1B1 and OATP1B3 that have the potential to predict transporter-mediated drug-drug interactions (DDIs). However, these compounds have often been identified from top-down strategies and have not been fully utilized as a substitute for traditional DDI studies. In an attempt to eliminate observer bias in biomarker selection, we applied a bottom-up, untargeted metabolomics screening approach in mice and found that plasma levels of the conjugated bile acid chenodeoxycholate-24-glucuronide (CDCA-24G) are particularly sensitive to deletion of the orthologous murine transporter Oatp1b2 (31-fold increase vs. wild type) or the entire Oatp1a/1b(-/-)cluster (83-fold increased), whereas the humanized transgenic overexpression of hepatic OATP1B1 or OATP1B3 resulted in the partial restoration of transport function. Validation studies with the OATP1B1/OATP1B3 inhibitors rifampin and paclitaxel in vitro as well as in mice and human subjects confirmed that CDCA-24G is a sensitive and rapid response biomarker to dose-dependent transporter inhibition. Collectively, our study confirmed the ability of CDCA-24G to serve as a sensitive and selective endogenous biomarker of OATP1B-type transport function and suggests a template for the future development of biomarkers for other clinically important xenobiotic transporters.

Original languageEnglish
Article number1933
Number of pages15
JournalPharmaceutics
Volume14
Issue number9
DOIs
Publication statusPublished - 13 Sep 2022

Bibliographical note

Funding: This research was funded in part by the National Institutes of Health grants R01CA238946
(S.H.), U24CA247648 (S.D.B.), and F31CA254151 (E.D.E.), by the OSU Comprehensive Cancer Center
Pelotonia foundation (S.D.B. and S.H.), and by the OSU Comprehensive Cancer Center Pelotonia
Fellowship Program (Y.L.). The content is solely the responsibility of the authors and does not
represent the official views of the funding agencies.

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